Introduction

Retroviruses, such as HIV, are particularly insidious. Most viruses infect a cell, force
it make many new copies of the virus, and then leave when the cell is used up.
Retroviruses, however, take a long-term approach to infection. They enter cells and
build a DNA copy of their genome. Then, they insert this viral genome into the cell's
own DNA. This integrated DNA can be used immediately to build more viruses, or it can stay
dormant, waiting for the best time to start virus production. This is one of the many
reasons that HIV is so hard to fight: it can lie waiting in these long-lived cells for years.

DNA Integration

Integrase is the enzyme that splices the viral DNA into a cellular chromosome. Four identical
copies of integrase grab the two ends of the viral DNA, creating a stable complex called
an intasome. The intasome then binds to the cellular DNA and performs a strand transfer
reaction, joining the viral DNA to the cellular DNA. The structure shown here (PDB entry
3os1)
includes four integrase subunits (in blue) and three short pieces of DNA that correspond to
the two viral DNA ends (red) and the cellular DNA (orange).
The two integrase subunits at the center (light blue) provide the active sites that cut
and join the DNA, and the outer pair of integrate subunits (dark blue) play a structural role.

Drugs Against HIV

Researchers have been studying HIV integrase for years, trying to understand how it
works so that they can design drugs to fight AIDS. This work has led to the
development of several effective drugs, including raltegravir, which is currently
being used to treat HIV infection. So far, it has proven difficult to crystallize
full-length HIV integrase and its complexes with DNA. The structures shown here are
from a related retrovirus, prototype foamy virus (PFV). Although PFV is harmless,
it is very similar to HIV integrase and provides an excellent model for studies of
retroviral integration.

Exploring the Structure

Structures of PFV integrase with DNA have revealed the critical steps of the
integration reaction. The two Jmol images presented here show two different
aspects of the structure. The first Jmol shows two structures: the complex just after
the intasome captures the target DNA (PDB entry
3os1)
and the complex after the strand transfer reaction (PDB entry
3os0). The
second Jmol shows a close-up view of the active site with the drug raltegravir (magenta) bound
to the two magnesium ions (green) that perform the reaction (PDB entry
3oya).
The structure reveals that inhibitors like raltegravir bind in the active site and displace one end
of the DNA strand.

Topics for further exploration

You can use the Structure Comparison tool to compare the PFV integrase
structures with the structures of different domains of HIV integrase.

Structures of several inhibitors with PFV and HIV integrase are available in the
PDB. You can use the Ligand Explorer (available in the asymmetric unit view) to
look at the interaction of these inhibitors with the integrase active site.